YCGA Provides World-Class DNA Sequence Analyses

From its beginnings in 2008 as a small next-generation DNA sequencing operation in the Microarray Resource of Yale’s Keck Foundation Biotechnology Resource Lab, the Yale Center for Genome Analysis (YCGA) has grown into a state-of-the-art facility that provides more than 40 different analyses to study genetic events. The introduction of new platforms, a substantial Mendelian Center grant from the National Institutes of Health (NIH), and the expertise of the center’s 23 staff members provide unparalleled opportunities for Yale investigators to collaborate on sequencing projects that have led to notable discoveries.

Located in a newly renovated building on Yale’s West Campus, the center boasts 10 Illumina HiSeq sequencing systems, each of which analyzes between 400 and 500 billion bases per week. While first- and second-generation sequencing technologies utilize amplification, YCGA now offers platforms capable of single-molecule sequencing in real time and rapid turnaround of data. The PacBio platform, one of three newly acquired third-generation sequencers, can sequence up to 10,000-base-long fragments at a time—a vast improvement over earlier technologies.

Shrikant Mane, Ph.D., director of YCGA

DNA sequencing can provide a deeper understanding of DNA and RNA than any other technology. While microarray technology revolutionized biomedical research, it has several limitations that DNA sequencing can overcome. The cost of sequencing, once prohibitive, is rapidly decreasing, so that performing sequencing at the genome level is becoming more affordable. YCGA will soon acquire four Ion Proton sequencers—powerful machines that have the potential to analyze the entire human genome in 24 hours for about $1,000. Exome analysis makes it possible to sequence protein-coding genes, which constitute one percent of the human genome but harbor 85 percent of disease-causing mutations. Whole-exome sequencing is significantly cheaper than whole-genome sequencing, and the price is declining; over the past year, the cost of sequencing a single human exome decreased from $2,500 to less than $600.

YCGA recently received $11.2 million from the NIH to establish the Center for Mendelian Genomics at Yale, one of three national centers that will study the genetic basis of rare disorders which afflict some 25 million Americans. The centers are expected to shed light on common diseases as well. For researchers, this is an unprecedented opportunity. “This work is carried out on a collaborative basis and at no cost to investigators for qualified samples,” said Shrikant Mane, Ph.D., director of YCGA. “We do the sequencing and analysis and give them the results.” YCGA is also performing the genomics for a multiyear collaboration with Gilead Sciences to accelerate the development of drugs against new cancer targets. DNA sequencing results will be used to define new driver genes, and map out pathways and mechanisms in tumors related to cell proliferation, inhibition of cell death, metastasis, and drug resistance.

In 2009, YCGA was the first center to use exome sequencing to make a clinical diagnosis. In a matter of days, investigators led by Richard Lifton, M.D., Ph.D., used whole-exome sequencing to identify a mutation in both copies of the gene associated with congenital chloride diarrhea in an infant. The center is now CLIA-certified for exome analysis, qualifying it to perform diagnostic testing.

Utilized by 120 pis from 38 departments, YCGA’s sequencing platforms have helped unravel genes and pathways involved in such disorders as brain malformations, hypertension, Gaucher disease, and squamous-cell carcinoma. In the past year, research conducted in collaboration with the center has led to the following breakthroughs:

A team led by Ruth Halaban, Ph.D., discovered a mutation in the RAC1 gene that plays a role in melanoma and is the third most frequent mutation, occurring in about nine percent of melanomas caused by UV exposure. The newly discovered pathway could be a potential target for the development of new therapies (Nature Genetics).

Using whole-exome sequencing, Matthew State, M.D., Ph.D., uncovered three genes that almost certainly contribute to autism, with the likelihood of discovering additional genes as sequencing efforts continue (Nature).

Whole-exome sequencing was also used by Lifton’s group to identify mutations in two genes that play a role in hypertension and electrolyte homeostasis (Nature).

“There is a very strong collaboration between Yale researchers and the Center, and that is why we are so successful,” said Mane. Technological advancements and increased capability will hopefully lead not only to continued discoveries in basic biology and the genetics of disease, but ultimately to new and better treatments.

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